Our long-term goal is to identify the neuronal mechanisms of elevated sympathetic outflow in rats with HS intake and cardiovascular diseases linked to salt retention, and provide new targets for treatments of salt-sensitive- hypertension and congestive heart failure. The objective here is to determine the role of endoplasmic reticulum (ER) stress in PVN in regulating SNA and neuronal activity and how ER stress modulates the SK currents to contribute to the increase in neuronal activity and sympathetic outflow in rats with HS intake. Our central hypothesis is that ER stress diminishes SK current within pre-sympathetic PVN neurons to increase their excitability, which may underlie the mechanisms of elevated sympathetic outflow in rats with HS intake. The rationale for the proposed research is that, once the mechanism is known how 1) ER stress in the PVN regulates sympathetic outflow in rats with a HS diet and 2) ER stress modulates SK currents among pre-sympathetic PVN neurons to regulate the neuronal excitability in rats with a HS diet, the data will contribute to new and innovative approaches to the prevention and treatment of cardiovascular diseases linked to salt retention, including salt-sensitive hypertension and congestive heart failure. We will test our central hypothesis and accomplish the overall objective by pursuing the following specific aims: Aim 1. To determine the role of PVN ER stress in regulating in vivo SNA and the role of SK channels in mediating the sympathetic responses elicited by PVN ER stress in both NS and HS treated rats. Our working hypothesis is that PVN ER stress contributes to the elevated sympathetic outflow in rats with a long-term HS diet through the mechanisms of down-regulation of SK channel function. Aim 2. To determine the effect of ER stress on the intracellular Ca2+ hemostasis, in vitro discharge of PVN neurons and the role of SK channels in mediating the ER stress-induced changes of neuronal activity in both NS and HS treated rats. Our working hypothesis is that increased PVN ER stress contributes to the increased neuronal activity in rats with HS intake through the mechanisms of reduced SK currents. Aim 3. To establish an integrated research and educational program in integrative physiology. This aim is expected to diversify university research infrastructure by introducing both in vivo and in vitro electrophysiology techniques and integrative physiology approaches in rodent animals and promoting integrative education and discovery-based learning for undergraduate and graduate students at Michigan Technological University.